Although cdk4-null-mutant mice highlight the importance of the CDK4/CYCLIN D1 complex in breast tumors and provide evidence to suggest that small molecule inhibitors of CDK4 kinase activity could be effective in the treatment of human disease, the importance of mutations in the CDK4 locus in human cancer was first underscored by discoveries which showed that germline mutations in this gene which abolish the ability of the encoded protein to bind to p16INK4A result in a predisposition of individuals to the development of melanoma [84, 85]. This evidence concerns the gene CDK4 and melanoma.